Fig. 10

Proposed model. Upon systemic LPS-challenge, TLR4 is stimulated in microglial cells favouring microglial activation and the acquisition of M1 phenotype. Top arm: Subsequently, TLR4 stimulation and the co-stimulation of DRD3 in astrocytes promotes their activation and the acquisition of a pro-inflammatory profile, characterized by high iNOS expression. Furthermore, DRD3 signalling in inflammatory astrocytes induces the generation of a mediator (still non-identified) which attenuates Fizz production by M2 microglia, thus favouring the function of M1 microglia and their neurotoxic consequences. Bottom arm: TLR4 stimulation in the absence of DRD3 signalling in astrocytes seems to render these cells unresponsive. Thereby, the absence of DRD3 signalling results in increased production of Fizz1 and consequently in a neuroprotective environment